Patent GB-850826-A (GB)
Title: Acid addition salts of esters of piperidyl phenyl methanol and processes for their production
Filed: 1957-09-17
Abstract: The invention comprises acid addition salts of the racemates and optically active isomers of esters of 2-piperidyl phenyl methanol (form B) of the general formula: <FORM:0850826/IV(b)/1> wherein R represents hydrogen, methyl or ethyl.  Specified salts are the hydrohalides, phosphate, sulphate, nitrate, maleate, fumarate, citrate, tartrate, methane sulphonate and ethane disulphonate.  They may be prepared by the following methods using the racemate or isomers of the named piperidyl phenyl methanol reagent: (1) esterification of an acid addition salt of the alcohol (form B) by known methods for the esterification of salts of amino-alcohols without concomitant acylation of an amino-group; (2) chlorination of the alcohol (form A or mixture of A and B) or its acid addition salt and converting the resulting 1-chloro-1-phenyl-1-(2-piperidyl) methane salt into the desired amine ester (form B) salt either by (a) hydrolysis and esterification of the resulting amino-alcohol (form B) in the form of an acid addition salt or (b) reaction with at least 2 moles of a metal salt of the acid R COOH, followed if desired by the conversion of the resulting acid salt into another salt; (3) treatment of a (1-RCO-2-piperidyl) phenyl methanol of form A or B with a strong acid to effect transposition of the RCO-group and yield the desired strong acid addition salt, heating being necessary when a form A reagent is used and preferred when a form B reagent is used; (4) reduction of the pyridyl ring in the corresponding <FORM:0850826/IV(b)/2> in acetic acid, the resulting acetate salt being converted if desired to another salt.  The salts of the racemic esters may be separated by direct resolution.  The products have nervous stimulant properties.  Examples include the preparation of (1) 1-acetoxy-1-phenyl-1-(2-piperidyl) methane hydrochloride by esterification of the amino alcohol (form B) hydrochloride with acetyl chloride-acetic anhydride mixture; (2) the corresponding 1-propionoxy compound using propionyl chloride; (3) and (4) the product of (1) by reacting 2-piperidyl phenyl methanol (form A) hydrochloride with thionyl chloride, isolating the resulting 1-chloro-1-phenyl-1-(2-piperidyl) methane.  HCl and hydrolysing it with crushed ice or aqueous AgNO3 and esterifying the amino alcohol (B form) as in (1); (5) the product of (1) by reducing 2-pyridyl phenyl ketone using a Pt. catalyst in acetic acid, converting the resulting amino alcohols (forms A and B) into their hydrochlorides and chlorinating, hydrolysing and acylating as in (4); (6) the product of (1) by heating the 1-chloro-methane hydrochloride intermediate of (3) with excess silver acetate in acetic acid and thereafter adding ethereal HCl; (10) the product of (1) by treating 1-(1-acetyl-2-piperidyl)-1-phenyl methanol (form A) in benzene with HCl and heating the product of 115 DEG  C; (13) 1-formyloxy-1-phenyl-1-(2-piperidyl methane hydrochloride as in (10) using the corresponding 1-formoxy piperidyl reagent; (14) the product of (1) by catalytically hydrogenating 1-acetoxy-1-phenyl-1-(2-pyridyl) methane in acetic acid and subsequently adding hydrochloric acid.  Laevo-rotatory 2-piperidyl phenyl methanol (form B) is obtained by chlorination followed by hydrolysis of the hydrochloride d-rotatory 2-piperidyl phenyl methanol (form A) itself obtained by catalytic hydrogenation of a rotatory 2-pyridyl phenyl methanol which is obtained by resolution of the racemic alcohols with d-tartaric acid.  L-rotatory 2-piperidyl phenyl methanol can also be obtained by resolution of the racemate with (-)dibenzoyl tartaric acid.  D-rotatory 2-piperidyl phenyl methanol (form B) can be obtained from 1-2-pyridyl phenyl methanol by the first method described above.  The amido starting material used in (10) is prepared by heating 2-piperidyl-phenyl methanol (form A) with acetic anhydride.  2-piperidyl phenyl methanol (A+B forms) is obtained by catalytic hydrogenation of 2-pyridyl phenyl ketone.